The principal component of the extracellular deposits in Alzheimer's disease is the amyloid-beta peptide (Ap). However, much remains to be learned about mechanisms through which Ap disturbs the properties of neurons, ultimately leading to cell dysfunction and death. The discovery and understanding of Amyloid-beta peptide Binding Alcohol Dehydrogenase (ABAD) may clarify the pathogenesis of this elusive disease. Our approach is to combine the use of in vitro hippocampal slices and neuronal cultures with in vivo animals. This strategy offers the advantage of identifying changes in synaptic transmission in a preparation with intact neuronal circuits (slice), of giving depth to the knowledge of these changes in a more simplified system with the unique possibility of having direct access to both the pre-and the post-synapticsite (cell culture), andfinally of determining whether it is possible to re-establish normal learning and memory by counteracting the effects of these changes in an in vivo complex neuronal system (the whole animal). The following aims will be addressed: a) to identify changes of synaptic transmission induced by ABAD/Ap interaction, b) to characterize mechanisms through which ABAD-Ap interaction leads to disruption of synaptic function, c) to identify whether ABAD/Ap interaction interferes with the adenylyl- cyclase(AC)/cAMP/cAMP-dependent-protein-kinase (PKA)/cAMP-regulatory-element-binding (CREB) pathway, a nd d) t o determine w hether a t reatment w ith peptides antagonizing A BAD-Ali interaction is capable of protecting mAPP mice against cognitive and synaptic impairments. Upon the completion of these studies, we will clarify whether and how ABAD/Ap interaction damages synaptic and cognitive function. The importance of analyzing the contributions of ABAD to Ap- induced cell stress is that inhibition of their interaction with Ap might provide a novel means for neuroprotective therapy at a time when cellular damage is still reversible. Project 3 will work closely with Projects 1-2 &4, and will obtain technical assistance from Core B and Core C. Collaborative interactions will include: exchange of reagents/techniques related to ABAD biology (Project 4), evaluation of cellular stress (Projects 1-2),generation of Tg mice (Core B), and behavioral and pathologic analysis (Core C).